RU2371434C1 - 2-(9-anthrylmethyl)amino-1[2-(1-pyrrolidinyl)ethyl]benzimidazole-fluorescent chemosensor on h+cations - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to new derivatives of 1,2-disubstituted 2-aminobezimidazole, and more specifically to 2-(9-anthrylmethyl)amino-1-[2-(1-pyrrolidinyl)ethyl]benzimidazole of formula I:

, which have properties of fluorescent chemosensor on H⁺ cations.

EFFECT: obtaining new fluorescent chemosensor on H⁺ cations.

1 dwg, 1 ex

Description

The invention relates to new derivatives of a number of 1,2-disubstituted 2-aminobenzimidazole benzimidazoles, namely to 2- (9-anthrylmethyl) amino-1- [2- (1-pyrrolidinyl) ethyl] benzimidazole of the formula I:

possessing the properties of a fluorescent chemosensor for H ⁺ cations.

Currently, a fairly large number of compounds are presented by the authors as effective chemosensors for hydrogen cations (JFCallan, APde Silva, DCMagri. Luminescent sensors and switches in the early 21st century. Tetrahedron, 2005, No. 36, p.8551-8558; BABren, Fluorescent and photochromic chemosensors, Advances in Chemistry, 2001, No. 12, pp. 152-1174; B. Valeur, I. Leray. Design principles of fluorescent molecular sensors for cation recognition. Coord. Chem. Rev., 2000, v .205, No. 1, p.3-40), contain a receptor, a complexing fragment responsible for the selective binding of the substrate, and a fluorophore, the so-called “signal” fragment of the chemosensor molecule whose optical properties change when the receptor interacts with the substrate. The function of receptors in proton chemosensors is performed by various nitrogen-containing structures - azaheterocycles, azacraunethers, azapodandes, calixarenes. In most cases, the so-called PET effect (Photoinduced Electron Transfer) is manifested in these systems - photoinduced electron transfer (G.J. Kavarnos. Fundamentals of Photoinduced Electron Transfer. NY, Wiley-VCH, 1993, 359 p.). The receptor at the sensor, based on the PET effect, is an electron donor, and the fluorophore is an acceptor. When a molecule is excited, an electron is transferred from the highest occupied molecular orbital (HOMO) of the fluorophore to the lower free molecular orbital (LUMO). This allows an electronic transition from the HOMO of the donor receptor to the HOMO of the acceptor-fluorophore, thereby causing quenching of the fluorescence of the latter. During complexation, a sharp decrease in the energy level of the HOMO receptor occurs, which leads to the fact that electron transfer to the HOMO fluorophore becomes energetically disadvantageous. There is a free transition of the excited electron from LUMO to the HOMO of the fluorophore and the sensor begins to fluoresce. The effectiveness of such chemosensors is evaluated by two factors - the degree of change in the initial fluorescence intensity upon addition of the substrate and the selectivity of detection of a specific cation.

High interest in chemosensory systems for determining the content of H ⁺ cations is caused by the possibility of their use for determining the basicity of various physiological objects (X. Gao, Y. Zhang, B. Wang. New boronic acid fluorescent reporter. Compounds. 2. A naphthalene-based on- off sensor functional at physiological pH, Org. Lett., 2003, No. 24, p. 4615-4618). At the same time, dialkylaminoaclyl derivatives of benzimidazole-2-amine and anthracene are interesting in terms of their own biological activity (C. Wang, J.-G. Delcros, J. Biggerstaff, O. Panstiel. Molecular requirements for targeting the polyamine transport system. Synthesis and biological evaluation of polyamine-anthracene conjugates. J. Med. Chem., 2003, No. 13, p. 2672-2682; RAGardner, J.-G. Delcros, F. Konate, F. Breitbeil, B. Martin, M. Sigman , M. Huang, O. Panstiel. N ^1- Substituent effects in the selective delivery of polyamine conjugates into cells containing active polyamine transporters. J. Med. Chem., 2004, No. 24, p. 6055-6069; B.A. Anisimova, I.E. Tolpygin, V.I. Minkin, A.A. Spasov, A.V. Stepanov, N.V. Arkova, L.V. Naumenko, V.I. Petrov. 9-substituted 2- salts halogenophenyl midazo [1,2-a] benzimidazoles and halides of 1-substituted 3-galogenfenatsil-2-aminobenzimidazole, and their compositions having rheological properties. № RF Patent 2290404, 2006 YG).

In 2003, 2-methyl-6- (4-methyl-1-piperazinyl) benzo [de] isoquinoline-1,3-dione was proposed by the authors (J. Gan, K. Chen, C.-P. Chang, H. Tian, Luminescent properties and photo-induced electron transfer of naphthalimides with piperazine substituent. Dyes and Pigments, 2003, p.21-28) as an effective fluorescent sensor for H ⁺ cations. When this compound interacts with an acid (however, the authors in this article are silent about which acid was used), the initial fluorescence increases by a factor of 76. Sensor selectivity has not been investigated.

The synthesized and studied chemosensor for H ⁺ cations - 2,7-bis (4-dimethylaminophenyl) -9- (cycloheptatrienylidene) fluorene (Z. Wang, G. Zheng, P. Lu. 9- (Cycloheptatrienylidene) fluorene derivative: appreciable ratiometric pH sensor and computing switch with NOR logic gate. Org. Lett., 2005, No. 17, p.3669-3672) is a class of connections that is very interesting from the point of view of sensory dynamics. When changing the pH of the solution (sulfuric acid was used) containing this sensor from 7.06 to 4.00, the fluorescence is quenched by more than four times, and further acidification to pH 0.97 leads to a flare up of 27 times at pH 4. 00 and 6.5 times at pH 7.06. A similar "on-off" of fluorescence under the influence of pH is claimed by the authors as the basis for a possible recording of information.

One of the most effective fluorescent sensors for H ⁺ cations is ethyl 4- (5- (4- (dimethylamino) phenyl) -1- (perfluorophenyl) -4,5-dihydro-3-pyrazolyl) benzoate (C.J. Fahrni, L. Yang, DGVanDerveer. Tuning the photoinduced electron-transfer thermodynamics in 1,3,5-triaryl-2-pyrazoline fluorophores: X-ray structures, photophysical characterization, computational analysis and in vivo evaluation. J. Am. Chem. Soc. , 2003, No. 13, p. 3799-3812). When protonating with normal sulfuric acid, the initial fluorescence flares up 160 times. However, in this case, the authors also did not study the interaction of the obtained sensor with other cations.

Among the fluorophore-containing benzimidazoles, 3- [2-diethylamino) ethylamino] benzimidazo [2,1-a] benz [de] isoquinolin-7-one is known which exhibits chemosensory activity with respect to H ⁺ cations. During protonation, the quantum yield of fluorescence changes depending on the pH of the medium (A.P. de Silva, HQNGunaratne, PLMLynch, AJPatty, GLSpence. Luminescence and charge transfer. Part 3. The use of chromophores with ICT (internal charge transfer) excited states in the construction of fluorescent PET (photoinduced electron transfer) pH sensors and related absorption pH sensors with aminoalkyl side chains. J. Chem. Soc., Perkin Trans. 2, 1993, p. 1611-1616).

In the series of 1,2-disubstituted 2-aminobenzimidazole, compounds are known that have different types of biological activity, for example, antihistamine action (M. Menzer, G. Laban, H.-G. Kazmirowski, P. Meisel, E. Kretzschmar. Verfahren zur herstellung von 2-amino-benzimidazol-derivaten. DD 281383, 1990), antiviral (FMSommen, KJLMAndries, JEGGuillemont, KPM-J. Meersman, JFALacrampe, FEJanssens. Respiratory syncytial virus replication inhibitors. WO 0100611, 2001) and others .

The closest in structure is 1- (4-fluorobenzyl) -2- (4-piperidyl) aminobenzimidazole, a Norastemizole preparation with antihistamine activity (Y. Hong, RP Bakale, CH Senanayake. Methods for synthesizing 2-substituted imidazoles. WO 98 / 46571, 1998; DA Handley, Y. Hong, RP Bakale, CH Senanayake. Norastemizole. Drugs of the Future. 1998, vol. 23, No. 9, p. 966).

The technical result of the invention is a new derivative in the series of 1,2-disubstituted 2-aminobenzimidazole, exhibiting a new for this series property of a highly efficient fluorescent chemosensor for H ⁺ cations.

The technical result is achieved by the compound of formula I, the synthesis of which consists in the interaction of 2-amino-1- [2- (1-pyrrolidinyl) ethyl] -

benzimidazole with 9-anthraldehyde and reduction of the obtained 2- (9-an-trilmethylene) amino-1- [2- (1-pyrrolidinyl) ethyl] benzimidazole with sodium borohydride to 2- (9-anthrilmethyl) amino-1- [2- ( 1-pyrrolidinyl) ethyl] benzimidazole (I).

The structure of all synthesized compounds was proved by elemental analysis, data of IR and ¹ H NMR spectra. In the IR spectrum of compound I, shot in liquid paraffin, there is a stretching vibration band of the secondary amino group at 3320 cm ^-1 . The ¹ H NMR spectrum of amine I contains signals from the proton of the amino group in the form of a broadened signal (δ 8.68), as well as a doublet from the CH ₂ group (δ 5.60, J 3.3 Hz) directly associated with the anthracene fragment.

The following is the synthesis method of the proposed compound.

Example 1. 2- (9-Antrylmethyl) amino-1- [2- (1-pyrrolidinyl) ethyl] benzimidazole (I)

A mixture of 2.06 g (10 mmol) of 9-anthraldehyde and 2.30 (10 mmol) of 2-amino-1- [2- (1-pyrrolidinyl) ethyl] benzimidazole (V.A. Anisimova, Yu.V. Koshchienko, B.M. Pyatin, N.I. Avdyunin, O.A.Samsonov, V.K. Rykov, M.K. Starovoitov.Method for the production of 2-amino-1-amino-alkylbenzimidazoles derivatives.Certificate No. 1149592, 1984 .) in 70 ml of ethanol is boiled for 6 hours. To a solution of 2- (9-anthrylmethylene) amino-1- [2- (1-pyrrolidinyl) ethyl] benzimidazole in ethanol, 0.95 g (25 mmol) of sodium borohydride are added after heating. The solution was stirred, diluted with water and the excess borohydride was neutralized with acetic acid. The precipitate formed is filtered off, washed with water and dried in air. Yield 3.50 g (83.2%). _Mp = 170-171 ° (acetonitrile). IR spectrum, ν, cm ^-1 : 3320, 1460, 1355. NMR spectrum ¹ H, δ, ppm: 0.91-1.12 (4H, m, CH ₂ CH ₂ ); 1.80-2.00 (4H, m, N (CH ₂ ) ₂ ); 2.60-2.73 (2H, m, NCH ₂ ); 3.80-3.92 (2H, m, HCH ₂ ; 5.60 (2H, d, CH ₂ , J 3.3 Hz); 6.96-8.54 (13H, m, arom H); 8.68 (2H, broad s, NH). Found,%: C 79.89; H 6.75; N 13.36. C ₂₈ H ₂₈ N _4. Calculated,%: C 79.97; H 6 , 71; N, 13.32.

The study of chemosensory properties

Research Methods. Assessment of the sensory ability of compound I was carried out according to the fluorescence spectra in the region of local fluorescence of anthracene. For this, a calculated five-fold molar excess of trifluoroacetic acid or metal acetate (Zn ²⁺ , Cd ²⁺ , Cu ²⁺ , was added to a solution of compound I (c = 5 × 10 ^-7 mol / L)

_флуор=414 нмWith ²⁺ , Ni ²⁺ , Pb ²⁺ , Hg ²⁺ ), or mixtures thereof, and the solution was stirred until the salt was completely dissolved. Then, fluorescence spectra were recorded at a wavelength

_fluor = 414 nm

_возб=360 нм): исходного раствора и растворов, содержащих помимо соединения I другие катионы. Съемка спектров люминесценции проводилась на спектрофлуориметре Hitachi 650-60.(

_exc = 360 nm): stock solution and solutions containing, in addition to compound I, other cations. The luminescence spectra were recorded on a Hitachi 650-60 spectrofluorimeter.

The calculation of the relative change in fluorescence intensity was carried out according to the formula: OIIF = I / I ₀ , where

I ₀ is the initial fluorescence intensity of the solution of compound I;

I is the fluorescence intensity of the solution of compound I after adding a five-fold molar excess of the cation.

Test results

A study of the spectral properties of amine I revealed its high sensory activity with respect to H ⁺ cations.

_возб.=360 нм (три индивидуальных максимума в области 390-440 нм и плечо 460-470 нм). В спектре испускания этого соединения также наблюдается полоса при 470-600 нм, соответствующая образованию эксимера.Chemosensor I due to the manifestation of the PET effect has a very weak fluorescence of anthracene type in neutral solutions of acetonitrile when excited by light

_exc. = 360 nm (three individual maxima in the region of 390-440 nm and a shoulder of 460-470 nm). The emission spectrum of this compound also shows a band at 470-600 nm, corresponding to the formation of an excimer.

Complexation with various cations through the use of the electron density of nitrogen atoms substantially modifies the thermodynamics of the PET effect, which leads to a change in the fluorescence intensity. The addition of acetates Cu ²⁺ , Co ²⁺ , Ni ²⁺ , Pb ²⁺ , Hg ²⁺ to the solution of sensor I causes a slight attenuation of the fluorescence intensity, while H ⁺ ions sharply increase the fluorescence intensity (I / I ₀ = 480) (cm .Drawing).

The selectivity of this sensor was shown when a mixture of cations was added to the initial amine I solution: H ⁺ , Zn ²⁺ , Cd ²⁺ , Cu ²⁺ , Co ²⁺ , Ni ²⁺ , Pb ²⁺ , Hg ²⁺ (each of the cations was taken in a five-fold molar excess relative to compound I). In this case, there is an increase in the relative fluorescence intensity (flaring up) by 470 times. As can be seen, the deviation of the fluorescence intensity of the solution of compound I with the addition of a mixture of cations (H ⁺ , Zn ²⁺ , Cd ²⁺ , Cu ²⁺ , Co ²⁺ , Ni ²⁺ , Pb ²⁺ , Hg ²⁺ ) from the solution of compound I with the addition of trichloroacetic acid (H ⁺ ) is negligible and indicates a high selectivity of this fluorescent chemosensor with respect to H ⁺ ions. The addition of triethylamine, taken in an equivalent amount (relative to the added acid), to the acid acetonitrile solution of amine I leads to a complete restoration of the initial fluorescence intensity, which indicates the reversibility of the protonation of sensor I and the possibility of its reuse.

Studies have shown that 2- (9-anthrylmethyl) amino-1- [2- (1-pyrrolidinyl) ethyl] benzimidazole (I) is a highly sensitive selective fluorescent sensor for H ⁺ cations.

Claims (1)

2- (9-Antrylmethyl) amino-1- [2- (1-pyrrolidinyl) ethyl] benzimidazole of the formula I